Functional and Structural Cerebellar-Behavior Relationships in Aging.

Objective Preterm birth alters typical brain development due to complex exposures related to neonatal illness, pain management, and brain injury. Despite an increased understanding of neonatal brain injury on developmental outcomes, the association of cerebellar maturation with school‐age motor and cognitive function remains incompletely understood. The current study evaluated neonatal clinical factors associated with regionally specific cerebellar volumes and white matter pathways at 8 years of age in children born preterm (24–32 weeks of gestational age). Methods Neuroimaging, clinical, and behavioral data were collected from 130 children born very preterm (24–32 weeks' gestational age) at BC Women's Hospital. Cerebellar subregions were automatically segmented using CerebNet, and cerebellar white matter connectivity was assessed using tractography. The relationships between cerebellar subregion volumes and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and motor neurodevelopmental outcomes related to cerebellar volume and connectivity were also investigated. Results Neonatal clinical factors including mechanical ventilation, number of invasive procedures, and opioid exposures were associated with reduced cerebellar volumes in specific subregions. Acute neonatal mortality risk (i.e., SNAPPE‐II) was negatively associated with cerebellar connectivity at 8 years. Reduced cerebellar volumes and structural connectivity were related to poorer cognitive and motor outcomes. Interpretation In very preterm children, neonatal illness severity and exposure to invasive procedures and opioids are associated with reduced cerebellar volumes, connectivity, and poorer neurodevelopmental outcomes at 8 years.

ABSTRACTThe cerebellum, traditionally associated with motor control, is increasingly recognized for its involvement in higher‐order cognitive functions. However, the role of cerebellar subregions in cognition remains underexplored, as are the roles of genetic factors on cerebellar structure and brain‐behavioral associations. The primary goal of this study was to investigate the relationship between cerebellar subregion volumes and cognitive performance. A secondary aim was to quantify the genetic contributions to cerebellar structure and determine the degree to which any brain‐behavior associations were genetically mediated. 3T anatomic MRI data from N = 932 typically developing individuals from the Human Connectome Project were used for this study. Twenty‐seven cerebellar regions of interest (ROIs) were automatically parcellated using CerebNet. Three additional lobar‐level ROIs were derived from smaller measures. Nine functional domains (six cognitive and three motor) related to known or suspected cerebellar function were selected. Linear regression analyses were conducted to identify correlations between cerebellar volumes and cognitive outcomes, adjusting for age, sex, and overall brain volume. Univariate and bivariate quantitative genetic modeling was then performed in OpenMx. There were numerous statistically significant phenotypic associations between cognitive measures and cerebellar lobar and lobular volumes, particularly in the IPL, AL, bilateral cortices, left lobule V, right lobule VI, vermis, and vermis lobule VIII, each meeting the threshold of p < 0.02 across at least four out of nine cognitive domains. The vermis and vermis lobule VIII were of particular note, showing even stronger associations (p < 0.0009 across three domains). Cognitive measures were modestly heritable, and cerebellar ROIs were highly heritable. Quantitative genetic models suggested that brain–behavior associations are largely driven by shared environmental factors. Our findings identify novel associations between specific cerebellar subregions and cognitive performance, highlighting the vermis as a critical structure. We also provide a detailed map of the quantitative genetics of human cerebellar structure. Future studies are warranted.

In this study, we aimed to evaluate the importance of cerebellum in freezing of gait (FOG) pathophysiology. Due to the fundamental role of the cerebellum in posture and gait control, we examined cerebellar structural and functional connectivity (FC) in patients with PD and FOG. We recruited 15 PD with FOG (PD-FOG), 16 PD without FOG (PD-nFOG) patients, and 16 healthy subjects (HS). The FOG Questionnaire (FOG-Q) assessed FOG severity. Three tesla-MRI study included resting-state functional MRI, diffusion tensor imaging (DTI), and 3D T1-w images. We located seed regions in the cerebellar locomotor region, fastigial, and dentate nucleus to evaluate their FC. DTI parameters were obtained on the superior, middle, and inferior cerebellar peduncles. Global and lobular cerebellum volumes were also calculated. Cerebellar locomotor and fastigial FC was higher in cerebellar and posterior cortical areas in PD-FOG than in HS. FC of the cerebellar locomotor region with cerebellar areas positively correlated with FOG-Q. Dentate FC was lower in the prefrontal and parieto-occipital cortices in PD-FOG than in HS and in the brainstem, right basal ganglia, and frontal and parieto-occipital cortices than in PD-nFOG. DTI parameters in superior and middle cerebellar peduncles were altered in PD-FOG compared with PD-nFOG and significantly correlated with FOG-Q. There were no differences in cerebellar volumes between PD-FOG and either PD-nFOG or HS. Our results suggest that altered connectivity of the cerebellum contributes to the pathophysiology of FOG. FC of the cerebellar locomotor region and white matter (WM) properties of cerebellar peduncles correlate with FOG severity, supporting the hypothesis that abnormal cerebellar function underlies FOG in PD.

The cerebellum is highly sensitive to adverse environmental factors throughout the life span. Socioeconomic deprivation has been associated with greater inflammatory and cardiometabolic risk, and poor neurocognitive function. Given the increasing awareness of the association between early-life adversities on cerebellar structure, we aimed to explore the relationship between early life (ESES) and current socioeconomic status (CSES) and cerebellar volume. T1-weighted MRI was used to create models of cerebellar grey matter volumes in 42 adult neurologically healthy males selected from the Psychological, Social and Biological Determinants of Ill Health study. The relationship between potential risk factors, including ESES, CSES and cerebellar grey matter volumes were examined using multiple regression techniques. We also examined if greater multisystem physiological risk index-derived from inflammatory and cardiometabolic risk markers-mediated the relationship between socioeconomic status (SES) and cerebellar grey matter volume. Both ESES and CSES explained the greatest variance in cerebellar grey matter volume, with age and alcohol use as a covariate in the model. Low CSES explained additional significant variance to low ESES on grey matter decrease. The multisystem physiological risk index mediated the relationship between both early life and current SES and grey matter volume in cerebellum. In a randomly selected sample of neurologically healthy males, poorer socioeconomic status was associated with a smaller cerebellar volume. Early and current socioeconomic status and the multisystem physiological risk index also apparently influence cerebellar volume. These findings provide data on the relationship between socioeconomic deprivation and a brain region highly sensitive to environmental factors.

The cerebellum has established associations with motor function and a well-recognized role in cognition. In advanced age, cognitive and motor impairments contribute to reduced quality of life and are more common. Regional cerebellar volume is associated with performance across these domains and sex hormones may influence this volume. Examining sex differences in regional cerebellar volume in conjunction with age, and in the context of reproductive stage stands to improve our understanding of cerebellar aging and pathology. Data from 508 healthy adults (ages 18-88; 47% female) from the Cambridge Centre for Ageing and Neuroscience database were used here. CERES was used to assess lobular volume in T1-weighted images. We examined sex differences in adjusted regional cerebellar volume while controlling for age. A subgroup of participants (n = 370, 50% female) was used to assess group differences in female reproductive stages as compared to age-matched males. Sex differences in adjusted volume were seen across most anterior and posterior cerebellar lobules. Most of these lobules had significant linear relationships with age in males and females. While there were no interactions between sex and reproductive stage groups, exploratory analyses in females alone revealed multiple regional differences by reproductive stage. We found sex differences in volume across much of the cerebellum, linear associations with age, and did not find an interaction for sex and reproductive stage on regional cerebellar volume. Longitudinal investigation into hormonal influences on cerebellar structure and function is warranted as hormonal changes with menopause may impact cerebellar volume over time.

Gray-matter structural variability in the human cerebellum: Lobule-specific differences across sex and hemisphere

Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (β = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (β = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (β = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (β=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Neurotrophin-like immunoreactivity in the human pre-term newborn, infant, and adult cerebellum

Objectives: This study aimed to investigate the potential connectivity mechanism between the cerebellum and anterior cingulate cortex (ACC) and the cerebellar structure in primary dysmenorrhea (PDM).Methods: We applied the spatially unbiased infratentorial template (SUIT) of the cerebellum to obtain anatomical details of cerebellar lobules, upon which the functional connectivity (FC) between the cerebellar lobules and ACC subregions was analyzed and the gray matter (GM) volume of cerebellar lobules was measured by using voxel-based morphometry (VBM) in 35 PDM females and 38 age-matched healthy females. The potential relationship between the altered FC or GM volume and clinical information was also evaluated in PDM females.Results: PDM females showed higher connectivity between the left perigenual ACC (pACC) and lobule vermis_VI, between the left pACC and left lobule IX, and between right pACC and right cerebellar lobule VIIb than did the healthy controls. Compared with healthy controls, no altered GM volume was found in PDM females. No significant correlation was found between altered cerebellum–ACC FC and the clinical variables in the PDM females.Conclusion: PDM females have abnormal posterior cerebellar connectivity with pACC but no abnormal structural changes. ACC–cerebellar circuit disturbances might be involved in the PDM females.

BackgroundThe cerebellum’s role in neuromyelitis optica spectrum disorder (NMOSD) remains inadequately explored, despite its known contributions to cognition and motor function.MethodsThis multimodal neuroimaging study integrated voxel-based morphometry (VBM), resting-state functional MRI (fMRI), and diffusion tensor imaging (DTI) to characterize cerebellar gray matter volume (GMV), microstructure, and functional connectivity (FC) in 29 NMOSD patients and 25 matched healthy controls. Clinical assessments included the Expanded Disability Status Scale (EDSS) and Montreal Cognitive Assessment (MoCA).ResultsPatients exhibited significant cerebellar alterations, including GMV reduction in bilateral lobules VI/VIII and the vermis, decreased fractional anisotropy in Crus I, and altered FC between Crus I and occipital/frontal regions. Critically, the structural and microstructural impairments correlated with higher EDSS scores (*p < 0.05), while FC changes were associated with lower MoCA scores.ConclusionThese findings implicate the cerebellum in both motor disability and cognitive impairment in NMOSD, providing novel evidence for cerebellar pathology as a contributor to disease progression.

The extensive prenatal developmental growth period of the cerebellum renders it vulnerable to unhealthy environmental agents, especially alcohol. Fetal alcohol spectrum disorders (FASD) is marked by neurodysmorphology including cerebral and cerebellar volume deficits, but the cerebellar lobular deficit profile has not been delineated. Legacy MRI data of 115 affected and 59 unaffected adolescents and young adults were analyzed for lobular gray matter volume and revealed graded deficits supporting a spectrum of severity. Graded deficits were salient in intracranial volume (ICV), where the fetal alcohol syndrome (FAS) group was smaller than the fetal alcohol effects (FAE) group, which was smaller than the controls. Adjusting for ICV, volume deficits were present in VIIB and VIIIA of the FAE group and were more widespread in FAS and included lobules I, II, IV, V, VI, Crus II, VIIB, and VIIIA. Graded deficits (FAS < FAE) were consistently present in lobules VI; neither group showed volume deficits in Crus I or IX. Neuroradiological readings blind to diagnosis identified 20 anomalies, 8 involving the cerebellum, 5 of which were in the FAS group. We speculate that the regional cerebellar FASD-related volume deficits may contribute to diagnostically characteristic functional impairment involving emotional control, visuomotor coordination, and postural stability.

The extensive prenatal developmental growth period of the cerebellum renders it vulnerable to unhealthy environmental agents, especially alcohol. Fetal alcohol spectrum disorders (FASD) is marked by neurodysmorphology including cerebral and cerebellar volume deficits, but the cerebellar lobular deficit profile has not been delineated. Legacy MRI data of 115 affected and 59 unaffected adolescents and young adults were analyzed for lobular gray matter volume and revealed graded deficits supporting a spectrum of severity. Graded deficits were salient in intracranial volume (ICV), where the fetal alcohol syndrome (FAS) group was smaller than the fetal alcohol effects (FAE) group, which was smaller than the controls. Adjusting for ICV, volume deficits were present in VIIB and VIIIA of the FAE group and were more widespread in FAS and included lobules I, II, IV, V, VI, Crus II, VIIB, and VIIIA. Graded deficits (FAS < FAE) were consistently present in lobules VI; neither group showed volume deficits in Crus I or IX. Neuroradiological readings blind to diagnosis identified 20 anomalies, 8 involving the cerebellum, 5 of which were in the FAS group. We speculate that the regional cerebellar FASD-related volume deficits may contribute to diagnostically characteristic functional impairment involving emotional control, visuomotor coordination, and postural stability.

The notion that the cerebellum is devoted exclusively to motor control has been replaced by a more sophisticated understanding of its role in neurological function, one that includes cognition and emotion. Early clinical reports, as well as physiological and behavioral studies in animal models, raised the possibility of a nonmotor role for the cerebellum. Anatomical studies demonstrate cerebellar connectivity with the distributed neural circuits linked with autonomic, sensorimotor, vestibular, associative and limbic/paralimbic brain areas. Identification of the cerebellar cognitive affective syndrome in adults and children underscored the clinical relevance of the role of the cerebellum in cognition and emotion. It opened new avenues of investigation into higher order deficits that accompany the ataxias and other cerebellar diseases, as well as the contribution of cerebellar dysfunction to neuropsychiatric and neurocognitive disorders. Brain imaging studies demonstrate the complexity of cerebellar functional topography, revealing a double representation of the sensorimotor cerebellum in the anterior lobe and lobule VIII and a triple cognitive representation in the cerebellar posterior lobe, as well as representation in the cerebellum of the intrinsic connectivity networks identified in the cerebral hemispheres. This paradigm shift in thinking about the cerebellum has been advanced by the theories of dysmetria of thought and the universal cerebellar transform, harmonizing the dual anatomic realities of homogeneously repeating cerebellar cortical microcircuitry set against the heterogeneous and topographically arranged cerebellar connections with extracerebellar structures. This new appreciation of the cerebellar incorporation into circuits that subserve cognition and emotion enables deeper understanding and improved care of our patients with cerebellar ataxias and novel cerebellar-based approaches to therapy in neuropsychiatry.

In children with attention deficit hyperactivity disorder (ADHD) difficulty maintaining task focus may relate to the coordinated, negatively correlated activity between brain networks that support the initiation and maintenance of task sets (task positive networks) and networks that mediate internally directed processes (i.e., the default mode network). Here, resting-state functional connectivity MRI between these networks was examined in ADHD, across development, and in relation to attention. Children with ADHD had reduced negative connectivity between task positive and task negative networks (p = 0.002). Connectivity continues to become more negative between these networks throughout development (7–15 years of age) in children with ADHD (p = 0.005). Regardless of group status, females had increased negative connectivity (p = 0.003). In regards to attentional performance, the ADHD group had poorer signal detection (d′) on the continuous performance task (CPT) (p < 0.0001), more so on easy than difficult d′ trials (p < 0.0001). The reduced negative connectivity in children with ADHD also relates to their attention, where increased negative connectivity is related to better performance on the d′ measure of the CPT (p = 0.008). These results highlight and further strengthen prior reports underscoring the role of segregated system integrity in ADHD.

Abnormal cerebellar morphometry in abstinent adolescent marijuana users